Platelet aggregation constitutes the initial hemostatic response to curtail bleeding induced by vascular injury. However, pathological extension of this normal hemostatic process can lead to thrombus formation. The final, common pathway in platelet aggregation is the binding of fibrinogen to activated, exposed platelet glycoprotein IIb/IIIa (GPIIb/IIIa). Agents which interrupt binding of fibrinogen to GPIIb/IIIa, therefore, inhibit platelet aggregation. These agents are, therefore, useful in treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, unstable angina, re-occlusion following thrombolytic therapy and angioplasty, inflammation, and a variety of vaso-occlusive disorders. The fibrinogen receptor (GPIIb/IIIa) is activated by stimuli such as ADP, collagen, and thrombin exposing binding domains to two different peptide regions of fibrinogen: alpha-chain Arg-Gly-Asp (RGD) and gamma-chain His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (HHLGGAKQAGDV, .gamma.400-411). Since these peptide fragments themselves have been shown to inhibit fibrinogen binding to GPIIb/IIIa, a mimetic of these fragments would also serve as an antagonist. In fact, prior to this invention, potent RGDbased antagonists have been revealed which inhibit both fibrinogen binding to GPIIb/IIIa and platelet aggregation e.g., Ro-438857 (L. Alig, J. Med. Chem. 1992, 35, 4393) has an IC.sub.50 of 0.094 .mu.M against in vitro thrombin-induced platelet aggregation. Some of these agents have also shown in vivo efficacy as antithrombotic agents and, in some cases, have been used in conjunction with fibrinolytic therapy e.g., t-PA or streptokinase, as well (J. A. Zablocki, Current Pharmaceutical Design 1995, 1, 533).
Accordingly, it is an object of the invention to identify compounds which are antagonists of GPIIb/IIIa. It is another object of the invention to identify compounds which inhibit platelet aggregation by inhibiting the binding of fibrinogen to GPIIb/IIIa. Another object of this invention is to identify compounds which are useful for treating thrombotic disorders. Still another object of the invention is to identify methods for treating thrombosis disorders using the compounds of the present invention.
We now describe a series of triazolopyridine compounds which act as antagonists of GPIIb/IIIa and are useful for treating thrombotic disorders.